Evaluation of Blood-Based Exosomes as Biomarkers for Aging-Related TDP-43 pathology

INTRODUCTIONLimbic predominant age related TDP-43 encephalopathy (LATE) is a recently characterized brain disease that mimics Alzheimers disease (AD) clinically. To date, LATE is difficult to diagnose antemortem using clinical information or biomarkers. Recent studies suggest concentrations of exosomal protein cargo derived from neuronal and glial cells may serve as useful diagnostic biomarkers for AD and other neurodegenerative diseases. METHODSTDP-43 was evaluated in neuronal (NDE), astrocyte (ADE), and microglial derived exosomes (MDE). Exosome preparations were isolated from the plasma of research subjects with autopsy-confirmed diagnoses, including many with LATE. Quantified TDP-43 concentrations were compared to cohort that included healthy controls, mild cognitively impairment (MCI), and AD dementia with diagnoses other than LATE. RESULTSTDP-43 was significantly elevated in plasma ADEs derived from autopsy confirmed LATE-NC subjects, with or without comorbid AD pathology. Measurable levels of TDP-43 were also detected in exosome depleted plasma; however, TDP-43 levels were not significantly different between persons with and without eventual autopsy confirmed LATE-NC. No correlation was observed between exosomal TDP-43 levels with cognition-based variables, sex, and APOE carrier status. DISCUSSIONBlood-based exosomes, specifically measuring TDP-43 accumulation in ADEs, may serve as a powerful diagnostic tool to rapidly identify subjects who are currently living with LATE-NC.